Structural basis of agrin-LRP4-MuSK signaling
Structural basis of agrin-LRP4-MuSK signaling
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DOI：
10.1101/gad.180885.111
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发表时间：
2012-02-01
影响因子：
10.5
通讯作者：
Jin, Rongsheng
中科院分区：
文献类型：
--
作者：
Zong, Yinong;Zhang, Bin;Jin, Rongsheng
突触是神经回路的基本单元，可以实现复杂的行为。神经肌肉接头（NMJ）是运动神经元和肌肉纤维之间形成的突触，对理解突触发生和神经肌肉疾病的一般原理做出了巨大贡献。NMJ的形成需要神经聚集蛋白，一种运动神经元衍生的蛋白，其与LRP 4（低密度脂蛋白受体相关蛋白4）相互作用以激活受体酪氨酸激酶MuSK（肌肉特异性激酶）。然而，很少有人知道信号是如何从聚集蛋白到MuSK转导。在这里，我们提出了第一个晶体结构的聚集蛋白-LRP 4复合物，由两个聚集蛋白-LRP 4异二聚体。初始二元复合物的形成需要Z 8环，该Z 8环特异性地存在于神经元而非肌肉聚集蛋白中，并且通过两个额外的界面促进四聚体的协同形成。我们发现，四聚体复合物是必不可少的神经元聚集蛋白诱导的乙酰胆碱受体（AChR）集群。总的来说，这些结果提供了新的见解聚集蛋白-LRP 4-MuSK信号级联和NMJ的形成，并代表了一种新的受体酪氨酸激酶的激活机制。
Synapses are the fundamental units of neural circuits that enable complex behaviors. The neuromuscular junction (NMJ), a synapse formed between a motoneuron and a muscle fiber, has contributed greatly to understanding of the general principles of synaptogenesis as well as of neuromuscular disorders. NMJ formation requires neural agrin, a motoneuron-derived protein, which interacts with LRP4 (low-density lipoprotein receptor-related protein 4) to activate the receptor tyrosine kinase MuSK (muscle-specific kinase). However, little is known of how signals are transduced from agrin to MuSK. Here, we present the first crystal structure of an agrin-LRP4 complex, consisting of two agrin-LRP4 heterodimers. Formation of the initial binary complex requires the z8 loop that is specifically present in neuronal, but not muscle, agrin and that promotes the synergistic formation of the tetramer through two additional interfaces. We show that the tetrameric complex is essential for neuronal agrin-induced acetylcholine receptor (AChR) clustering. Collectively, these results provide new insight into the agrin-LRP4-MuSK signaling cascade and NMJ formation and represent a novel mechanism for activation of receptor tyrosine kinases.